To obtain an insight into the unusual host-virus interactions resulting in slowly evolving diseases, two natural viral infections of domestic animals are studied by simple methods of clinical observation, animal inoculation, serology, virology, and anatomic pathology. These diseases are (1) scrapie of sheep and goats and (2) Aleutian disease of ranch mink. Scrapie is a degenerative disease of the brain caused by an unconventional virus. Replication of the virus in central nervous tissue, which gives rise to the slowly progressive polioencephalopathy, is preceded by many months of replication in extraneural sites, notably lymphoreticular tissues and intestine. Observations on naturally infected lambs and experimentally inoculated fetal and newborn Suffolk sheep provided little information on the early events in the infectious process, especially those events that might bear on modes of natural transmission. This was so because of the long period between exposure to virus and its first detection by mouse innoculation, the only practical way for doing so. The lack of a more suitable detection method and the absence of an immune response to the infection continue to hamper study of this unusual infectious disease. Aleutian disease, caused by a parvovirus, is a chronic renal disease brought about by circulating virus-antibody complexes that become deposited in the glomeruli. Aleutian and non-Aleutian mink were found equally susceptible to infection with several strains of virus. The infection gave rise to viremia in all Aleutian mink but in only some non-Aleutian mink. Disease did not supervene, however, unless the viremia persisted beyond the first few months after exposure to virus. These findings emphasize the need to distinguish between infection and disease when efforts are made to understand the pathogenesis and epidemiology of Aleutian disease. Information obtained from these studies has implications for understanding comparable protracted human diseases.